Rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid (CCI-779, temsirolimus) has demonstrated significant inhibitory effects on tumor growth in both in vitro and in vivo models. CCI-779 binds to and forms a complex with the cytoplasmic protein FKBP, which inhibits an enzyme, mTOR (mammalian target of rapamycin, also known as FKBP12-rapamycin associated protein [FRAP]). Inhibition of mTOR's kinase activity inhibits a variety of signal transduction pathways, including cytokine-stimulated cell proliferation, translation of mRNAs for several key proteins that regulate the G1 phase of the cell cycle, and IL-2-induced transcription, leading to inhibition of progression of the cell cycle from G1 to S. CCI-779 has been demonstrated to be effective in multiple applications, including but not limited to inhibition of central nervous system cancer, leukemia, breast cancer, prostate cancer, melanoma, gliomas, and glioblastoma.
Polyethylene glycol (PEG) is a linear or branched, neutral polymer available in a variety of molecular weights and is soluble in water and most organic solvents. The preparation and use of pegylated rapamycin derivatives has been described in U.S. Pat. Nos. 5,955,457 and 6,432,973. In the processes described therein, hydroxyesters of rapamycin (prepared as described in the literature, e.g., U.S. Pat. Nos. 5,362,718 and 6,277,983, and U.S. Patent Publication No. US 2005-0033046 A1) are acylated and the resulting compound is reacted with a polyethylene glycol.
Use of the processes to prepare mono-pegylated CCI-779 yields a pair of stereoisomers. Such stereoisomers require further separation steps are required to obtain a single isomer of mono-pegylated CCI-779, which is difficult and costly. What is needed are processes enabling the preparation of a readily separated isomer of mono-pegylated CCI-779.